Abstract: Pretreatment operated in a flow through (FT) mode offers several performance advantages compared to pretreatment in non FT configurations at the same temperature and residence time. The impact of hydrothermal FT pretreatment severity on pretreatment and solubilization performance metrics was evaluated for three milled feedstocks (corn stover, bagasse, and poplar), highlighting key performance trends and advantages. Experimental results with sugarcane bagasse showed that the typical tradeoff between increased fiber reactivity and increased sugar degradation could be substantially mitigated by carrying out pretreatment in a FT mode. However, operation of FT configurations in a practical context is challenging. Arranging a reactor of biomass in a flow type configuration at elevated temperature and pressure is mechanically complex. Higher water usage compared to non-flow configuration may dilute sugar streams and increase energy consumption. These crucial challenges to practical implementation were studied to define the feasible regions of hot water FT pretreatment. Furthermore, a model incorporating both kinetics and mass transfer was developed to simulate performance of pretreatment in plug flow, counter-current flow, cross flow, discrete counter-current and partial FT configurations. Using sugarcane bagasse without particle size reduction, the instability of the reactor during pretreatment above 140 kg/m3 set an upper bound on the allowable concentration for continuous stable flow. Simulated results compared well to the literature for bagasse pretreated in both batch and FT configurations. A variety of FT configurations resulted in very low sugar degradation and high solids reactivity, but sequential plug and cross flow configuration was recommended for fluid mechanical reasons. Economic considerations were favorable to practical commercial implementation of FT pretreatment. Sugar dilution was not a limiting factor, and energy consumption was managed through energy integration within the biorefinery. It was possible to integrate a plant making ethanol from sugarcane bagasse and trash to a plant making sugar from sugarcane, while maintaining energy self-sufficiency.